Antimicrobial peptides represent widely distributed, ancient weapons, produced by living organisms to defend themselves against a variety of rivals, for survival and spread. Plant and animal, antimicrobial peptides are part of their innate immune defenses. Antimicrobial peptides are also produced by various microorganisms including bacteria, termed bacteriocins (Hassan et al., J. Appl. Microbiol., 2012, 113: 723-736). Antimicrobial peptides provide advantages for the producer against competing bacteria in the environment or during infections. To defeat the invading or competing microorganisms, the antimicrobial peptides target a fundamental difference between the membranes of prokaryotes and of eukaryotes (Zasloff, Nature, 2002, 415: 389-395). The exposed surfaces of bacterial membranes are populated by negatively charged phospholipids whereas the outer leaflet of plants and animals membranes is composed of neutral lipids. Eukaryotic and prokaryotic antimicrobial peptides share common features: they are small (20 to 50 amino acids), cationic, amphiphilic or hydrophobic, facilitating their interactions with the negatively charged bacterial membranes on which they can form pores causing leakage of cellular solutes or disrupt membrane integrity, triggering cell death (Melo et al., Nat. Rev. Microbiol., 2009, 7: 245-250).
Various bacteria have also the ability to produce toxic peptides from toxin-antitoxin modules in response to environmental stimuli including persister cells formation, stress resistance, protection against viral infections or biofilm formation (Ghafourian et al., Curr. Issues Mol. Biol., 2013, 16: 9-14). Type I toxin-antitoxin pairs encode hydrophobic toxic peptides whose synthesis is repressed by antisense RNAs during growth, and they are widely distributed in bacteria (Fozo et al., Nucleic Acids Res., 2010, 38: 3743-3759; Pinel-Marie et al., Cell Rep., 2014, 7: 424-435). Functional Type I toxin-antitoxin pairs expressed by Staphylococcus aureus, a major human pathogen, have been identified (Sayed et al., Nat. Struct. Mol. Biol., 2011, 19: 105-112). The RNA pair lies on opposite strands, one RNA encodes a 30-residue PepA1 toxic peptide and the other convergent antisense RNA inhibits toxin production by preventing its synthesis. PepA1 structure was solved by NMR spectroscopy and is a long bent, interrupted helix, presumably forming pores to alter membrane integrity. In vivo, PepA1 localizes at the bacterial membrane, triggers S. aureus death and also lyses human erythrocytes at similar concentrations (Sayed et al., J. Biol. Chem., 2012, 287: 43454-43463). Considerable efforts are currently implemented to develop modified antimicrobial peptides as anti-infective agents (Wilmes and Sahl, Int. J. Med. Microbiol., 2014, 304: 93-99), especially because of the alarming emergence of pathogens resistant to various drugs used in clinics. Natural antimicrobial peptides act rapidly and locally and cannot be used as therapeutics because of their degradations by numerous proteases.
The present Applicant has previously reported peptides derived from the SprA1-encoded bacteriocin isolated from Staphylococcus aureus with antimicrobial properties (WO 2013/050590). However, these peptides had the disadvantage of having cytolytic properties